Multiple myeloma (MM) is a plasma cell neoplasm that affects thousands of people each year. Currently, there is no cure for MM, few if any patients survive, and even with a strong regimen of conventional chemotherapy and radiation, life expectancy is on average three years. The recent development of novel chemotherapeutics that inhibit components of the proteasome have proven very successful in extending progression-free and overall survival. These drugs inhibit the ubiquitin-proteasome degradation pathway through binding to one or more of the protease active sites within the proteasome.
The ubiquitin-proteasome system (UPS) plays an essential role in protein quality control by degrading unwanted or misfolded proteins within cells. The UPS helps maintain cell homeostasis and regulates numerous processes including cell cycle, apoptosis, transcription, and DNA repair. Inhibition of the UPS induces apoptosis by preventing degradation of pro-apoptotic proteins, thereby facilitating activation of programmed cell death. Inhibiting the UPS pathway was validated as a clinical target with the FDA approval of bortezomib (marketed as Velcade, Millennium Pharmaceuticals), followed by carfilzomib (marketed as Kyprolis, Onyx Pharmaceuticals), and most recently ixazomib (marketed as Ninlaro, Takeda Pharmaceuticals), all approved for treatment of MM.
Protein degradation through the proteasome (i.e., proteolysis) occurs through a long complex pathway. Proteolysis is initiated through ATP-dependent activation of ubiquitin by E1 proteins. Through a series of steps involving E2 and E3 proteins, the protein destined for degradation becomes tagged with ubiquitin. The ubiquitin-tagged protein undergoes several rounds of ubiquitin ligation resulting in polyubiquitination. The 19S regulatory system of the proteasome recognizes polyubiquitination, and then traps and unfolds the polyubiquitinated protein, which is then translocated into the active site of the 20S complex, and expelled as oligopeptides. It is the proteasome regulatory particle lid subunit (Rpn11) zinc(II) (Zn2+) metallo-isopeptidase subunit within the 19S complex that hydrolyzes the polyubiquitin bound to the protein and releases the ubiquitin into the cytoplasm to be recycled. This crucial ubiquitin recycling step catalyzed by Rpn11 is necessary for protein degradation to occur, and inhibition of this crucial step is a target for proteasome inhibition and cell apoptosis.